Treatment of diseases of the human eye is often accomplished through the topical administration of therapeutic agents. Any topical method of drug delivery must take into account and attempt to overcome many inherent physiological systems that operate to protect and maintain the vital front surfaces of the eye. For example, the cornea and conjunctiva are coated with mucin and bathed in a complex aqueous fluid derived mainly from the lacrimal glands. The region between the lids of the normal eye--the interpalpebral space--is covered by the preocular tear film, a very thin (generally less than 40.mu.M) liquid layer covering the cornea and conjunctiva. The preocular tear film is provided on its anterior surface with a thin film of lipids derived from the Meibomian glands that open along the lid margin. Because the tear film is dynamic and subject to contamination, the tear film is continually replaced, the effete tear residues being forced from the eye through the pair of puncta and associated canaliculi at the medial corner of the eye by blinking.
In order to have therapeutic effect, a drug or other compound must generally pass into the eye through the cornea. Problematic to topical delivery of drugs is the fact that the cornea is less permeable than the conjunctiva. Further, the surface area of the conjunctiva is highly vascularized, and in surface area is some 14 times greater than the surface area of the cornea. For these reasons, the transconjunctival loss of instilled drugs is considerable. Further, water soluble drugs are quickly eliminated from the eye surface through tear outflow, a process that is often accelerated in the diseased eye, and topical delivery of drugs to the eye in sufficient quantity and for sufficient periods is often difficult. Thus, the effectiveness of prior art methods of topical drug application is often limited.
The most common known topical delivery of ophthalmic drugs is accomplished using water-based compositions, either as a solution or a suspension. Such compositions are generally delivered as drops or as a wash directly to the eye surface. Because such aqueous compositions are quickly eliminated from the eye, various attempts have been made to enhance the contact time and/or drug delivery characteristics by employing a variety of water-soluble polymers, both synthetic and natural. For stability, these water-polymer preparations must contain a preservation system when intended for a multiple dose use. Further, most compositions must be buffered, usually to an acidic range. Examples of stabilized solutions and tear substitutes are disclosed in U.S. Pat. Nos. 4,407,791 to Stark; 4,409,205 to Shively; and 5,075,104 to Gressel et al. When instilled in the eye, the drug preparation usually overwhelms the resident tear volume, resulting in an initial loss both of some drug and the resident tear constituents. Further, the relatively cool temperature and acidic pH of the drug preparation produces a strong blink reflex coupled with reflex tearing , thereby resulting in further loss of the drug preparation from the eye surface by outflow.
Although the use of aqueous vehicles is a common and widespread means of topical delivery, the use of such a delivery system has resulted in a number of problems. First, the very nature of the delivery system, in particular its aqueous and irritating characteristics, results in a rapid loss of drug from the eye, necessitating frequent and repetitive reintroduction of the drug-bearing composition to the eye. This is not only inconvenient to the patient, but results in less efficacious treatment because of the difficulty in maintaining a more or less continuous delivery of drug through the cornea to the eye. This difficulty of delivery is further compounded by the loss of drug preparation across the larger and more permeable vascular conjunctival surface. Preservatives and stabilizing compounds can also result in tissue damage to the cornea and conjunctiva.
In attempts to avoid the problems associated with aqueous drug delivery, suspensions of insoluble drug preparations have been used, resulting in longer drug action through the slow dissolution of particles trapped in the cul de sacs. However, the use of ophthalmic suspensions has its own set of problems, primarily inaccurate dosages due to inadequate patient resuspension.
Water-insoluble ointments have also been used as vehicles for drug delivery. However, the use of ointments has many attendant problems, not the least of which is discomfort and loss of visual acuity due to the excessively thick and uneven layer produced by the ointment on the cornea. In addition, ointments are difficult to apply since the delivery method requires application of the ointment to the tarsal conjunctiva of the everted lower lid.
In addition to purely fluid vehicles, such as aqueous solutions, suspensions and ointments, solid vehicles in the form of drug-releasing inserts have also been utilized to deliver drugs to the eye surface. Many of these devices and methods are discussed in Pavan-Langston (1973) and Lamberts (1973). Examples of such inserts include the PVA inserts of Maichuk and the Ocuserts1/2 of Alza. Some inserts are hydrophilic contact lenses that have been impregnated with a drug that is released to the corneal surface over time after lens insertion. In other cases, the insert actually dissolves slowly to release the drug. The use of inserts however is problematic. They are cumbersome, increase the risk of eye infection by agents carried into the eye on the insert, and are expensive. Further, it is not clear that inserts actually achieve as high or as prolonged a delivery of drug as is sometimes claimed. For example, much of the drug released from an insert is still likely to be taken up by the conjunctiva and pass thereafter into the general circulation with little or no therapeutic benefit for the eye. Further, the irritation resulting from the use of the insert probably results in increased flow of lacrimal fluid, thereby increasing the likelihood that the drug will be washed out of the eye.
A significant problem associated with all known methods of topical drug delivery stems from the muscular coordination required of the patient for self-application. Both soluble aqueous vehicles and aqueous suspensions are generally delivered through drops to the eye. Ointments require precise delivery to the inside portion on an eyelid, while ocular inserts of various types require finger delivery of an object into the eye. Each of these manipulations can be especially difficult for the elderly and can result in serious injury to the eye when the drug is delivered to the eye with too much force.
One ophthalmological disease that has proved especially susceptible to treatment by the method just described is dry eye, (also known as keratoconjunctivitis sicca), is a common ophthalmological disorder affecting millions of Americans each year. The condition is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. It is one of the most common of human eye diseases and is generally treated through the topical delivery of a variety of therapeutic agents.
Dry eye may afflict an individual in varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation when debris lodge between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Good reviews of dry eye syndrome and standard methods of treatment may be found in Dohlman (1971) and Lemp (1973).
Although it appears that dry eye may result from a number of unrelated pathogenic causes, all presentations of the syndrome share a common effect, the breakdown of the pre-ocular tear film, which results in dehydration of the exposed outer surface and many of symptoms outlined above.
Practitioners have taken several approaches to the treatment of dry eye. One common approach has been to supplement and stabilize the preocular tear film using so-called artificial tears. Another approach has been the use of ocular inserts that function variously to provide a tear substitute or to stimulate endogenous tears.
Examples of the tear substitution approach include the use of buffered, isotonic saline solutions, aqueous solutions containing water soluble polymers that render the solutions more viscous and thus less easily shed by the eye. Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids. Examples of these treatment approaches are disclosed in U.S. Pat. Nos. 4,131,651 to Shah et al.; 4,370,325 to Packman; 4,409,205 to Shively; 4,744,980 and 4,883,658, both to Holly; 4,914,088 to Glonek; and 5,057,104 to Gressel et al.
United States Patents directed to the use of ocular inserts in the treatment of dry eye include U.S. Pat. No. 3,991,759 to Urquhart. The use of ocular inserts is also discussed in detail in Lamberts (1980).
Another recent approach involves the provision of lubricating substances in lieu of artificial tears. U.S. Pat. No. 4,818,537 to Guo discloses the use of a lubricating, liposome-based composition. U.S. Pat. No. 4,966,773 discloses the use of microfine particles of one or more retinoids.
Aside from the above efforts, which are directed primarily to the alleviation of symptoms associated with dry eye, also known are methods and compositions directed to treatment of the dry eye condition. For example, U.S. Pat. No. 5,041,434 discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye condition in post-menopausal women.
Although these approaches have met with some success, problems in the treatment of dry eye nevertheless remain. The use of tear substitutes, while temporarily effective, generally requires repeated application over the course of a patient's waking hours. It is not uncommon for a patient to have to apply artificial tear solution ten to twenty times over the course of the day. Such an undertaking is cumbersome and time consuming, increases the exposure of the eye to preservative agents and can be very expensive.
The use of ocular inserts is also problematic. Aside from cost, they are often unwieldy and uncomfortable. Further, as foreign bodies, they pose a risk of acting as a vector for infectious organisms. In situations where the insert does not itself produce and deliver a tear film, artificial tears must still be delivered on a regular and frequent basis. Indeed, Pavan-Langston (1973) has concluded that, as a rule, ocular inserts are not very effective in the treatment of many dry eye conditions.
In view of the foregoing, there is a clear need for a reliable, effective, method of topical delivery of a therapeutic agent to the cornea that is both easy to administer and long acting.